Epidemiologic evidence suggests that women with diabetes have increased risk of breast cancer and that diabetes may dramatically increase mortality in patients with cancer. Importantly, African-American and Hispanic/Latina women are disproportionately affected by diabetes and its complications. Concurrently, these women have worst outcome from breast cancer. Diabetes and cancer share many risk factors, but potential biologic links between the two diseases are incompletely understood. Our preliminary studies have provided new insights into how high glucose (HG) functions in breast epithelial cells. Exposure of cultured transformed (MCF-7) and normal (MCF-10A) breast epithelial cells to clinically relevant levels of glucose dramatically suppresses the tumor suppressor p53 acetylation, and, consequently, additively promotes tumor cell proliferation and abrogates DNA damage-induced apoptosis. Importantly, activation of nuclear phosphatase PP2Cd plays a role in this process. In addition, we for the first time demonstrate that BRAC1 forms a complex with p300 and p53, and an increased phosphorylation of BRAC1 by DNA damage enhances the recruitment of p53 to p300 and facilitates subsequent p53 acetylation. Upon activation by HG, PP2Cd dephosphorylates BRAC1 and inhibits its up-regulatory effect on p53 acetylation. These results may not only provide explanation for increased epithelial proliferation and tumorigenesis by hyperglycemia, but also increased breast cancer risk by diabetes. Based on these results we hypothesize that hyperglycemia, via a pathway that involved in PP2Cd activation, suppresses the tumor suppressor BRCA1 and p53 function and inhibits DNA damage-induced apoptosis and cell cycle arrest, inducing proliferation in the epithelium and the initiation and development of breast cancer. This hypothesis will be tested in three specific aims: (1) To explore the mechanisms underlying HG-induced PP2Cd activation; (2) To investigate the molecular mechanism by which PP2Cd dephosphorylates BRAC1 and antagonizes p53 acetylation in breast epithelial cells; (3) To characterize the effects of hyperglycemia on the development and chemotherapy of breast cancer in vivo using streptozotocin (STZ)-induced or high fat diet/STZ-induced diabetic nude mice bearing MCF-7 cells and breast cancer specimens from patients with or without diabetes. These studies set the stage for investigating this novel mechanism connecting diabetes and breast cancer with a goal of defining a new pathway and providing additional targets for therapy. Breast cancer in particular affects a large sector of African-American and Hispanic women and constitutes a significant financial burden for the society. Thus, studying the influence of hyperglycemia on oncogenic signaling networks is a novel question with considerable translational implications and would be a significant step in shedding light on this health disparity.